Atherosclerosis is an inflammatory disease, occurring preferentially in arterial regions associated with disturbed flow while sparing the undisturbed flow regions. We have shown that exposure of endothelial cells (EC) to disturbed flow conditions stimulates production of bone morphogenic protein 4 {BMP4), which induces inflammatory responses in ECs and hypertension in mice. Recently, while studying the mechanism of BMP4 action, we made the surprising paradoxical observation that siRNA-mediated knockdown of the BMP receptor type II (BMPRII), instead of blocking the inflammatory response as we initially hypothesized, induces a striking inflammatory response in EC. We also found that BMPRII expression decreases as the atherosclerotic lesion advances in human coronary arteries. Similar observations were made in a novel model of flow-induced atherosclerosis using a partial ligation of the carotid artery in Apo-E null mice. Our preliminary results further show that BMPRII deficiency dramatically accelerates the development of atherosclerosis in the partially liqated model using BMPRir'ApoE''mice, while it is significantly blunted in p47phox-deficient ApoE-null mice (P47'^APOE )[unreadable] demonstrating the critical role of BMPRII and NADPH oxidases in the flow-induced atherosclerosis model. We also found that the pro-inflammatory cytokine TNFa decreases BMPRII expression, whereas the cholesterol lowering statins increase it in cultured endothelial cells. These intriguing findings led us to propose that loss of BMPRII may be a central event in lesion initiation and progression at sites of disturbed flow. Defining the underlying mechanisms through which BMPRII is involved in vascular inflammation and atherosclerosis is the specific goal of this application. The pathophysiological importance of BMPRII in vascular inflammation and atherosclerosis is not known. However, genetic mutations of BMPRII are a major cause of familial primary pulmonary hypertension. BMPRII contains a long cytoplasmic tail that binds more than 34 proteins including p50b NFKB, protein kinase Cp and cSrc. Studies suggest that the BMPRII may be a scaffolding protein that keeps the bound proteins inactive until activated by agonist binding, much like how caveolin-1 functions. Here, we will examine the hypothesis that BMPRII expression is downregulated by pro-atherogenic factors including TNFa and upregulated by anti-atherogenic conditions and drugs such as statins. The decrease in BMPRII expression unleashes the signaling proteins that are normally bound to the receptor and kept inactive, resulting in uncontrolled activation of vascular inflammation and subsequent atherosclerosis development in a NADPH oxidase-dependent manner. We will test the hypothesis using ECs and mouse models in four Aims. Aim 1 will define the changes in BMPRII expression in flow-disturbed atherosclerotic lesions in ApoE'''mice fed a high fat diet with or without a partial ligation of the carotid artery. Aim 2 will determine the mechanisms by which statins and TNFa regulate BMPRII expression in ECs and ApoE-null mice. Aim 3 will detennine the mechanisms by which BMPRII knockdown induces inflammation in ECs. Aim 4 will determine the effect of reduced BMPRII expression on inflammation and atherosclerosis using BMPRir''_ApoE-null mice fed a high fat diet. Successful completion of these studies will provide novel insight into understanding the atherogenic mechanisms caused by the loss of BMPRII in the vessel wall, and how atherogenic conditions alter BMPRII levels in endothelial cells. This new knowledge will provide a novel therapeutic and diagnostic target to treat and prevent atherosclerosis.